Driven to Exhaustion?

Science Signaling  20 Sep 2011:
Vol. 4, Issue 191, pp. ec262
DOI: 10.1126/scisignal.4191ec262

During infection, antigen-specific T cells expand in numbers and gain effector functions. Later, most cells die off, leaving a small pool of memory T cells; however, during chronic viral infection, effector cells fail to develop into memory cells but become “exhausted” and poorly secrete effector cytokines. Exhausted cells are characterized by the presence of inhibitory receptors, such as PD-1, that inhibit T cell receptor (TCR) signaling. Tim-3 is another membrane glycoprotein receptor found on exhausted T cells; however, unlike PD-1, it does not have inhibitory motifs through which it could recruit proteins to inhibit TCR signaling. Through reporter assays for the transcription factors NFAT and NF-κB, which are downstream of the TCR, Lee et al. showed that ectopic expression of mouse Tim-3 in a human T cell line enhanced basal and TCR-dependent reporter activity, which depended mostly on two membrane-proximal tyrosine residues in the cytoplasmic tail of Tim-3, and did not require its extracellular domains. Tim-3 underwent basal and TCR-stimulated phosphorylation at particular tyrosine residues, and in vitro kinase assays showed that Tim-3 was phosphorylated by Fyn and another Src family kinase, Lck. Coexpression of either kinase with Tim-3 in kinase-deficient cells enhanced NFAT and NF-κB reporter activity compared with that in cells expressing Tim-3 alone. Doxycycline-induced expression of the gene encoding Tim-3 in a T cell line enhanced TCR-dependent activation of phospholipase C–γ1 and secretion of the cytokine IL-2, two indicators of T cell activation. Finally, retroviral overexpression of Tim-3 in primary mouse T cells enhanced their secretion of interferon-γ, indicating increased effector function. Together, these data suggest that Tim-3 enhances TCR signaling, leading the authors to speculate that this could be a mechanism by which the glycoprotein induces T cell exhaustion.

J. Lee, E. W. Su, C. Zhu, S. Hainline, J. Phuah, J. A. Moroco, T. E. Smithgall, V. K. Kuchroo, L. P. Kane, Phosphotyrosine-dependent coupling of Tim-3 to T-cell receptor signaling pathways. Mol. Cell. Biol. 31, 3963–3974 (2011). [Abstract] [Full Text]